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From Irina A. Kozeretska, Svitlana V. Serga, Alexander K. Koliada and Alexander M. Vaiserman,

Epigenetic Regulation of Longevity in Insects. In: Heleen Verlinden, editor, Advances in Insect

Physiology, Vol. 53, Oxford: Academic Press, 2017, pp. 87-114.

ISBN: 978-0-12-811833-7

© Copyright 2017 Elsevier Ltd

Academic Press

Provided for non-commercial research and educational use only. Not for reproduction, distribution or commercial use.

CHAPTER FOUR

Epigenetic Regulation ofLongevity in InsectsIrina A. Kozeretska*, Svitlana V. Serga*, Alexander K. Koliada†,Alexander M. Vaiserman†*Taras Shevchenko National University of Kyiv, Kyiv, Ukraine†D.F. Chebotarev Institute of Gerontology, NAMS, Kyiv, Ukraine

Contents

1. Introduction 882. Mechanisms of Epigenetic Regulation Across Insect Species 893. Developmental Epigenetic Programming of Caste-Specific Differences in

Longevity in Social Insects 913.1 DNA Methylation 923.2 Alternative Splicing 943.3 Histone Modifications 943.4 Regulation by miRNAs 943.5 Caste-Specific Difference in Gene Expression Patterns 95

4. Modification of Aging and Longevity in Drosophila by Modulating EpigeneticPathways 984.1 Histone Methyltransferases and Demethylases 984.2 Histone Acetyltransferases 994.3 Histone Deacetylases 994.4 HDAC Inhibitors 99

5. Transgenerational Epigenetic Inheritance of Life Span and Longevity-AssociatedTraits in Drosophila 104

6. Conclusions 107References 108

Abstract

When studying aging, an important issue is that it is a complex process influenced by alarge number of environmental and genetic factors. The effects of these factors are dif-ficult to investigate because they influence and modify each other. Therefore, it is dif-ficult to examine these factors using complex mammalian models like rodents. Thereby,a large body of biogerontological research is based on simple model organisms such asinsects. Such models are particularly useful in an exceedingly complex field such as epi-genetics of aging. A high degree of conservation exists between insect and mammaliangenomes in terms of both epigenetic mechanisms and signalling pathways associated

Advances in Insect Physiology, Volume 53 # 2017 Elsevier LtdISSN 0065-2806 All rights reserved.http://dx.doi.org/10.1016/bs.aiip.2017.03.001

87

Author's personal copy

http://dx.doi.org/10.1016/bs.aiip.2017.03.001

with aging processes. Insect models proved to be very valuable for the study of epige-netic mechanisms mediating the influence of environmental factors on development,aging, neurodegeneration, cancer and infectious disorders. Therefore, the identificationof epigenetic processes underlying aging and aging-related pathological conditions ininsect models would be an important step towards the further development of treat-ment strategies to promote human health span and longevity.

1. INTRODUCTION

Aging is considered to be associated with an increase in the number of

cells that undergo senescence. This makes an organism progressively less

capable of withstanding stress and maintaining homeostasis, and therefore

more susceptible to disease (Dillin et al., 2014). It is a complex process that

depends on the interaction of multiple genetic and environmental processes.

In humans, longevity has been shown to be moderately heritable (�25%)

(Christensen et al., 2006). Several studies also indicate that exceptional lon-

gevity is an inherited phenotype (Atzmon et al., 2005). A number of human

genes likely associated with longevity and thereby potentially used as targets

for medical intervention have been identified (de Magalhaes et al., 2012).

However, because of the complexity of longevity-associated phenotypic

traits, the nature of longevity inheritance is still poorly understood

(Christensen et al., 2006).

Insects represent a useful model for studying the genetics of aging. Many

insects have two or more distinct phenotypes determined by the same geno-

type, such as male and female adults, winged and nonwinged aphids or castes

of social insects (Simpson et al., 2011; Srinivasan and Brisson, 2012). More-

over, the benefits of using insect models for studying biological mechanisms

of aging include its relatively short life span, ease of maintenance, environ-

mental and genetic manipulations that alter life span, availability of stocks

containing altered genes, sequence of the full genome in several insect species

and clear distinction between developmental and adult stages (Helfand and

Rogina, 2003). In addition, almost all cells in adult insects are postmitotic.

Therefore, the age-related decline in cellular functions may be examined

without interference from newly dividing cells (Grotewiel et al., 2005).

Key postulated cellular and molecular mechanisms of aging include reac-

tive oxygen species-mediated oxidative damage to macromolecules, such as

DNA, proteins and lipids (Sanz, 2016), genome instability (Vijg and Suh,

2013), accumulation of advanced glycosylation end products, telomere

88 Irina A. Kozeretska et al.


shortening (Koliada et al., 2015) and cell senescence (Campisi and Robert,

2014). Recently, a crucial role of epigenetic mechanisms regulating gene

expression, including DNA methylation, histone modifications (methyla-

tion, acetylation, phosphorylation, etc.) and changes of noncoding micro-

RNAs (miRNAs), in aging processes has been highlighted (Pal and

Tyler, 2016). These research findings suggest that rather than being genet-

ically predetermined, the rate of aging and longevity are determined epige-

netically rather than by primary DNA sequence, and that nutrition and other

environmental influences may affect aging by modulating the epigenetic

information. Moreover, epigenetic transcriptional reprogramming can lead

to the formation of different longevity phenotypes which sometimes are

heritable across generations (Vaiserman, 2013).

Presently, a role of epigenetic processes in aging and longevity is being

actively studied in a number of experimental models. Highlighting the age-

related processes of epigenetic regulation in eukaryotic organisms is very

important for the development of strategies to increase the human health

span and longevity. The development of insect models in such studies allows

to reduce the costs and to promote research of basic aging-related processes,

which are conserved across wide taxonomic ranges (Mukherjee et al., 2015).

In this chapter, mechanisms of epigenetic gene regulation that control aging

and longevity of different insect species are summarized and discussed with

an emphasis on the insect models most frequently used in biogerontological

research, such as the honey bee, Apis mellifera and the fruit fly, Drosophila

melanogaster.

2. MECHANISMS OF EPIGENETIC REGULATIONACROSS INSECT SPECIES

In most eukaryotes, DNA methylation is the key epigenetic mecha-

nism for regulating gene expression. This mechanism is performed by

linking of a methyl chemical group to cytosine (Yamada and Chong,

2017). In different animal species, such linking is often performed in the

CpG dinucleotide contexts. Methylation transforms cytosine into

methylcytosine, which does not alter the DNA sequence but substantially

affects its interaction with proteins. Such chemical alterations are maintained

during DNA replication and are thus somatically heritable. DNA methyla-

tion is performed by a group of evolutionarily conserved enzymes referred to

as DNA methyltransferases (DNMTs). DNMT1 class methyltransferases

perform symmetrical methylation de novo of the newly synthesized

89Epigenetic Regulation of Longevity


DNA strand during replication and use the old strand as a template (Goll and

Bestor, 2005). The role of the DNA methyltransferase-2 (DNMT2)

enzymes is controversial, as it is unclear whether they function mostly as

nuclear DNA or cytoplasmic tRNA methyltransferases. It is also unclear

whether DNMT2 impacts development, as mice and fruit flies mutant for

dnmt2 do not exhibit altered phenotypes (Kunert et al., 2003; Okano

et al., 1998; Rai et al., 2007). Finally, DNMT3 are methyltransferases that

perform de novo DNA methylation (Liu et al., 2003).

DNA methylation is widespread across insect species, although excep-

tions exist. For example, in Diptera (flies and mosquitoes) such as

D. melanogaster, only 1% of the genome is methylated (Takayama et al.,

2014). This methylation usually occurs in specific 5bp sequence motifs that

are rich in CA and CT duplets but depleted of guanine. Methylation of the

gene body appears to associate with a lower expression level, and most genes

containing methylated regions within the coding parts have developmental

or transcriptional functions. DNMT2 is the only DNMT known from the

Drosophila genome. However, fly strains deficient for DNMT2 retain the

DNA methylation, which suggests the presence of other, possibly novel,

methyltransferases (Takayama et al., 2014). In other insect species, including

ants, bees, wasps, sawflies, cockroaches and termites, 5-methylcytosine is

likely the most common form of the epigenetic DNA modification,

although insects with DNA methylation do not always possess the ordinary

enzymatic machinery (Bewick et al., 2017). Anyhow, CpG methylation in

insects is much lower than in humans. Unlike humans, it tends to be primar-

ily concentrated in exons (Glastad et al., 2011). For instance, out of the

10 million CpG sites in the honey bee genome, only 70,000 (0.7%) are

found to be methylated (Lyko et al., 2010), while in humans the figure is

close to 70% (Strichman-Almashanu et al., 2002). DNA methylations in

CpG contexts has been shown to vary during insect development, as

shown, e.g. in A. mellifera and the red flour beetle, Tribolium castaneum, with

the highest levels observed in the embryos (Drewell et al., 2014; Feliciello

et al., 2013).

The interaction of proteins with DNA is also regulated by changes in

chromatin compaction through the histone tail modification. Acetylated

histone tails are more typical of relatively loose DNA packaging in the

nucleosomes, which increases the nucleic acid accessibility to various tran-

scription factors and thus promotes gene expression. Deacetylation, on the

other hand, is accompanied by opposite processes. These histone modifica-

tions are controlled by two enzyme families: histone deacetylases (HDACs)



and histone acetyltransferases (HATs). Experiments with HAT and HDAC

inhibitors both in mammals and insects have revealed a significant role of the

balance between HAT and HDAC activity in gene regulation during both

normal development and disease progression (Mukherjee et al., 2012).

miRNAs are another important group of epigenetic regulators. These

are short RNA molecules (18–22 nucleotides in length) that regulate gene

expression posttranscriptionally. The miRNA ‘seed sequence’ (nucleotides

2–8 at the 50 end) usually binds to a complementary site in the 30 untranslatedregion of mRNAs and inhibits the translational of the target mRNA or lead

to its degradation. In insects, miRNA biogenesis goes through several stages

and starts with transcription of the miRNA loci (Ylla et al., 2016). The

RNA-induced silencing complexes (RISCs) are constructed into large mul-

tiprotein effectors, binding to target transcripts and trigger their destruction.

In Drosophila, miRNAs have been found to play various roles in longevity-

related processes, such as development, apoptosis and maintenance of the

longevity-influencing intracellular bacterial endosymbiont, Wolbachia

(Lucas and Raikhel, 2013).

3. DEVELOPMENTAL EPIGENETIC PROGRAMMING OFCASTE-SPECIFIC DIFFERENCES IN LONGEVITY INSOCIAL INSECTS

Among all insect models which are used to research the aging pro-

cesses, social insects are likely the most attractive model systems for deeper

insight into this topic since they demonstrate a large plasticity of aging pro-

cesses across different castes (Maleszka, 2008; Yan et al., 2015). For example,

in A. mellifera unfertilized eggs develop into males (drones), while the fer-

tilized eggs develop into female queens or workers (Remolina and

Hughes, 2008). Thus, queens develop from eggs that are genetically not dif-

ferent from those developing into workers. Queens are, however, much

larger in size, have specialized anatomy, develop significantly faster and live

much longer than worker bees. The caste switching is determined by hor-

monal signals triggered by the quantity and quality of nutrition during the

third larval instar stage (Winston, 1987). Moreover, workers are sterile,

whereas queens are reproductive. Queens develop from larvae fed with a

nutritional mixture consisting of essential amino acids, lipids, proteins, vita-

mins and other compounds (royal jelly) until they enter metamorphosis

(Drapeau et al., 2006), while workers develop from larvae fed with a royal

jelly until the late instar stage (stage of mature larva) and then fed a worker



jelly (a mixture of glandular secretions, pollen and honey). The life span of

worker bees is about 15–38 days, while queens have a life span of about 1–2years (Remolina and Hughes, 2008). In another social insect species includ-

ing ants, wasps and termites, queens and workers also sometimes demon-

strate up to a 100-fold difference in longevity, with reproductive queens

having longer life span than nonreproductive workers (Keller and

Jemielity, 2006; Remolina et al., 2007). Through these features, social

insects provide a useful model to identify candidate pathways involved in

control of aging and longevity. In particular, the genome-wide study of gene

expression in castes of social insects markedly differing in life span is likely a

promising approach for the screening of genes involved in life span deter-

mination (Corona et al., 2005).

From studies performed on A. mellifera, it became evident that the queen

phenotype is driven by epigenetic reprogramming in developing larvae by

particular nutritional components contained in royal jelly (Foret et al., 2012;

Welch and Lister, 2014). Epigenetic modifications induced by specific envi-

ronmental cues during the early development have been demonstrated to be

persistent throughout the entire life cycle, thereby causing a process known

as ‘developmental programming’ (Lillycrop et al., 2014; Vaiserman, 2014).

Epigenetic modifications can be induced in a context-dependent manner in

response to both external and internal stimuli and can lead to context-

dependent programming effects through the persistent effects on gene reg-

ulatory cascades (Dickman et al., 2013). Feeding A. mellifera female larvae

with royal jelly leads, in general, to reduced levels of global DNA methyl-

ation and correlated alteration in gene expression along with elevated juve-

nile hormone (JH) levels. Such changes collectively cause formation of

highly reproductive and long-lived queen phenotype. Larvae fed with

less-nutritious worker jelly develop into short-lived and functionally sterile

worker bees. In the subsections later, we summarize the evidence for the role

of epigenetic mechanisms in developmental determination of the caste fate

in various social insect species.

3.1 DNA MethylationDNA methylation is a key mechanism involved in shifting the caste deve-

lopmental trajectories in A. mellifera and other social insects (Elango

et al., 2009; Maleszka, 2016; Standage et al., 2016). The methylation of

CpG islands in promoter gene regions is associated with transcriptional

silencing (Klose and Bird, 2006). This mechanism of epigenetic regulation



is, however, not universal across insect species. For example, low to zero

DNA methylation levels were detected in T. castaneum andD. melanogaster

(Lyko and Maleszka, 2011). Recent research, however, highlighted

the role of DNA methylation in different social insect species inclu-

ding the honey bee (Maleszka, 2016). All three main subfamilies of

DNMT enzymes, namely DNMT1, DNMT2 and DNMT3, are pres-

ented in A. mellifera (Maleszka, 2008). In most insects studied to date,

DNA methylation has been found to be predominantly restricted to cod-

ing exons and absent in the promoter regions (Maleszka, 2016; Patalano

et al., 2012).

In A. mellifera, the downregulation of DNMT3, which is a key driver in

epigenetic remodelling, was found to cause a profound shift in the caste fate

of developing larvae. Silencing the Dnmt3 expression in newly hatched lar-

vae by small interfering RNAs (siRNAs) caused changes in the larval devel-

opmental trajectories similar to those induced by royal jelly (Kucharski et al.,

2008). The decreased levels of DNA methylation were observed in several

genes in the heads of queen-destined larvae regardless of whether they were

hive-reared or generated via siRNA-caused DNMT3 silencing (Kucharski

et al., 2008; Maleszka, 2008). Differential DNA methylation patterns have

been observed between worker and queen brains/heads (Foret et al., 2012;

Lyko et al., 2010). Genes involved in insulin and JH pathways were shown

to be significantly overrepresented among the differentially methylated

genes. Several CpG sites in the hexamerin 110 gene encoding a storage pro-

tein have been shown to be differentially methylated between the worker

and queen larvae (Ikeda et al., 2011). It has also been found that the larval

dietary conditions may influence various methylation sites inside the dynactin

p62, a conserved gene responsive to nutritional cues (Shi et al., 2011). In a

subsequent study by Shi et al. (2013), significant differences in age dyna-

mics of the global DNA methylation levels were obtained among castes.

Most of these differentially methylated genes are involved in the biologically

important processes linked to development, reproduction and metabolic

regulation.

Evidence for the role of DNA methylation in the process of caste differ-

entiation has also been provided in several ant species. Ants were demon-

strated to have a full set of DNMTs and their genomes contain

methylcytosines (Bonasio et al., 2012). The caste- and allele-specific differ-

ences in methylation correlating with the allele-specific expression was

obtained in the Florida carpenter ant,Camponotus floridanus, and the Jerdon’s

jumping ant, Harpegnathos saltator (Bonasio et al., 2012).



3.2 Alternative SplicingAlternative splicing is a process by which different combinations of exons

from the same gene can be joined together to form various mature mRNA

isoforms and protein products. It has been proposed to be a potential mech-

anism for linking DNAmethylation and caste-specific gene regulation across

social insect species (Foret et al., 2012). Several caste-related patterns of CpG

methylation were shown to be enriched in exon regions, particularly in

splicing sites (Lyko et al., 2010). The association between DNAmethylation

and splicing sites was particularly evident for the genes belonging to the his-

tone gene family. Also in two ant species interaction between DNA meth-

ylation and alternative splicing in determining caste-specific developmental

pathways was confirmed (Bonasio et al., 2012). However, some authors sug-

gest that morphological and behavioural differences between castes might

rather be attributed to the production of caste-specific protein isoforms than

to transcriptional alterations per se (Glastad et al., 2011).

3.3 Histone ModificationsHistone modifications such as acetylation, methylation, phosphorylation,

ubiquitination and sumoylation are another crucial mechanism of epigenetic

regulation in social insects. This mechanism of epigenetic control operates in

a coordinated manner with DNA methylation to regulate gene expression.

Generally, methylation of DNA in promoter regions represses transcription,

while histone acetylation is linked with an activation of transcription

(Musselman et al., 2012). By profiling the genome-wide localization of his-

tone H3modifications, caste-specific differences in histone methylation pat-

terns were observed between the female worker and male castes in the ant

C. floridanus (Simola et al., 2013). The level of acetylation of lysine 27 of

histone H3 (H3K27ac) has been shown to be a strong predictor for caste

identity. The majority of genes identified to have different H3K27ac levels

between castes are associated with muscle development, sensory responses

and neuronal regulation. Moreover, HDAC inhibitors present in royal jelly

appear necessary for the development of bees towards queens (Spannhoff

et al., 2011).

3.4 Regulation by miRNAsEpigenetic regulation by miRNAs is suggested to be another important

mechanism for social insect caste differentiation. Significant age- and

caste-associated differences in the transcriptional patterns of miRNAs have



been observed (Weaver et al., 2007). Most genes in proximity to miRNAs

were demonstrated to be linked to gene ontology terms, such as ‘physiolog-

ical process’, ‘nucleus’ and ‘response to stress’. Interestingly, worker jelly was

found to be significantly enriched in complexity and abundance of miRNAs

relative to royal jelly (Guo et al., 2013). Most of these miRNAs are known

to be involved in regulation of mRNAs functionally related to the develop-

ment of the insects’ central nervous system. Worker and queen larvae con-

tain differentially expressed miRNAs. These miRNAs coincide with both

composition and relative expression levels of miRNAs present in worker

jelly. They have been found to be expressed two- to fourfold higher in

worker larvae as compared to queen larvae. The supplementation of royal

jelly with particular miRNAs resulted in significant changes in the levels

of mRNA expression in queen-destined larvae and also in morphological

traits of the emerging insects in a way characteristic to the worker phenotype

(Guo et al., 2013).

3.5 Caste-Specific Difference in Gene Expression PatternsCollectively, changes in epigenetic regulation result in modulation of gene

expression, thereby causing caste-biased phenotypes, such as long-lived

queens and short-lived workers (Chen et al., 2012; Evans and Wheeler,

1999, 2000). Most genes exhibiting differential patterns of expression

between the queen- and worker-destined larvae were demonstrated to be

involved in metabolic pathways (Barchuk et al., 2007; Corona et al.,

1999; Cristino et al., 2006; Evans and Wheeler, 1999, 2000). Most meta-

bolic enzymes were exhibited to be upregulated in queen-destined larvae

seemingly reflecting their increased growth rate during the late larval stage

(Begna et al., 2011). Some genes coding for proteins responsive for RNA

processing and translation were also demonstrated to be upregulated in

young queen larvae (Corona et al., 1999; Evans and Wheeler, 1999,

2000). In the genome-wide expressional profiling of the DNMT3-silenced

honey bee larvae, most genes differentially expressed among worker and

queen larvae were linked to hormonal regulation, energy transfer, protein

turnover, posttranslational modification, lipid transport, ribosomal biogen-

esis and other physiometabolic processes (Kucharski et al., 2008). In a trans-

criptome comparison byChen et al. (2012), over 70% among the 4500 genes

shown to be differentially expressed between the worker- and queen-

destined larvae were found to be more highly expressed in queen than in

worker larvae assuming that general levels of transcriptional activity during



differentiation are higher in queen larvae compared to worker ones. The

genome-wide transcriptional analysis conducted on the brains from the

same-aged virgin honey bee queens and both sterile and reproductive

workers has revealed significant differences in the expression levels for

�2000 genes between the queen and both worker bee groups, and much

smaller differences between the sterile and reproductive worker bees

(Grozinger et al., 2007). Importantly, several groups of genes shown to

be specifically involved in longevity-associated pathways in other species

were found to be differentially expressed between the worker and queen lar-

vae. Among them, there were genes responsible for the regulation of the

hypoxia pathway, such as HIFα/Sima, HIFβ/Tango and PHD/Fatig

(Azevedo et al., 2011), as well as genes potentially involved in the prevention

and repair of oxidative damage (Aamodt, 2009).

Caste-specific patterns of gene expression were also identified in social

insect species other than honey bee. These patterns appeared very similar

in A. mellifera and the bumblebee, Bombus terrestris (Pereboom et al.,

2005). For example, substantial age- and caste-related expression changes

of candidate genes associated with taxonomically widespread aging-related

pathways, such as Dnmt3, foraging, vitellogenin and coenzyme

Q biosynthesis protein 7, were demonstrated in B. terrestris (Lockett et al.,

2016). Also in several ant species such as Temnothorax longispinosus

(Feldmeyer et al., 2014) and Atta vollenweideri (Koch et al., 2013) caste-

specific gene expression patterns were identified. The enhanced expression

levels of genes responsible for somatic repair were observed in long-lived

queens compared to workers in ant Lasius niger (Lucas et al., 2016). In

another study with L. niger, 16 genes have been found to be differentially

expressed between adult queen and worker insects (Gr€aff et al., 2007).Among them, three genes upregulated in queens are known to be linked

to maintenance and repair of the soma, generally considered to be crucial

mechanisms of longevity determination. Moreover, genes encoding sirtuin

deacetylases and telomerase were shown to be upregulated in longer-lived

H. saltator reproductives (Bonasio et al., 2010).

Up to now, only one study was solely focused on genetic pathways

potentially involved in determining the social insect longevity (Corona

et al., 2005). In this research, the predictions of oxidative stress theory of

aging were tested. This theory postulates that production of highly reactive

free radicals and other reactive oxygen species leads to oxidative damage of

cellular components; thereby, the accumulation of oxidative damage is con-

sidered to be a proximate cause of aging (Sanz, 2016). To examine these



assumptions, Corona et al. (2005) determined the levels of expression of

eight genes encoding antioxidant defence system enzymes and also five

mitochondrial proteins in A. mellifera. The expression of antioxidant genes

decreased with age in queens, but not in workers. Therefore, the extraor-

dinary longevity of queen bees may be unlikely explained by increased anti-

oxidant capacity per se. Similar data indicating that increased level of

expression of antioxidant genes is most likely not necessary for the evolution

of the extended life expectancy in social insects, have been also obtained in

the ant L. niger (Parker et al., 2004). Specifically, adult queens had equal or

even lower levels of expression of the CuZnSod gene in thorax, head and

abdomen compared to those in short-lived female workers and male ants.

A schematic representation of hypothetical regulatory pathways responsible

for determining caste fate in A. mellifera is presented in Fig. 1.

Caste-specific epigeneticprogramming

Royal jelly

Worker jelly

Hypermethylation

Hypomethylation

Insulin/IGF-1EGRFTOR

Juvenile hormone

Fig. 1 Schematic representation of hypothetical mechanisms involved in developmen-tal programming of caste-specific differences in longevity in Apis mellifera. Under thishypothetical model, feeding of larvae with royal jelly results in reduced levels of globalDNA methylation and correlated alterations of gene expression and splicing. Thesechanges, in turn, trigger the endocrine response manifested in the activation of juvenilehormone, target of rapamycin (TOR), and epidermal growth factor receptor (EGFR) sig-nalling along with complicated and ambiguous changes in the insulin/insulin growthfactor 1 (IGF-1) pathway in the queen larvae. Collectively, these processes seem tobe contributing to the evolution of long-lived queen phenotype.



The extraordinary large differences in longevity between the genetically

identical worker and queen female castes substantially challenges our under-

standing of the processes mediating aging (Kramer et al., 2016) and provides

a unique perspective in investigating factors underlying variations in life span

both within and among species.

4. MODIFICATION OF AGING AND LONGEVITY INDROSOPHILA BY MODULATING EPIGENETICPATHWAYS

Since DNA methylation is practically absent in adult fruit flies, it is

generally believed that histone modifications are the primary mechanism

of epigenetic regulation in this model organism. However, while age-related

changes in histone acetylation and methylation in mammals have been

described repeatedly, studies of this phenomenon in D. melanogaster are

rather scarce.

4.1 Histone Methyltransferases and DemethylasesA number of studies on various organisms, including D. melanogaster,

showed age-dependent changes of histone methylation levels. These

changes are mainly related to the general decrease of amount of heterochro-

matin. Significant decrease in the enrichment of the heterochromatin-

repressive H3K9me3, H3K9me2 and heterochromatin protein 1 marks have

been found with age (Larson et al., 2012). Another study showed an increase

in the overall level of H3K9me3, but decrease at pericentric heterochroma-

tin regions. Such extensive alterations in repressive chromatin state were

associated with age-related changes in gene expression (Wood et al.,

2010). However, it should be noted that the increase in H3K9me3 levels

was observed in the heads of female flies, while the reduction in

H3K9me2 was seen in the whole bodies of mixed male and female flies.

It is therefore possible that the result depends on the cell type or sex-specific

alterations in histone methylation. Additionally, substantial reduction of his-

tone modifications linked to active transcription, such as H3K4me3 and

H3K36me3, at transcriptional start sites and over genes has been observed

in older flies. Such significant changes in methylation of histones can likely

lead to change in expression or activity of histone methyltransferases and

demethylases. Moreover, it was shown that heterozygous mutations in

two core subunits of Polycomb Repressive Complex 2, the histone H3

lysine 27 (H3K27)-specific methyltransferase E(z) and its partner, the



H3-binding protein ESC, result in increased longevity and reduced levels of

trimethylated H3K27 (H3K27me3) in adult flies (Siebold et al., 2010).

4.2 Histone AcetyltransferasesIn several studies, evidence has been obtained that aging and longevity in

D. melanogaster may be affected by modulation of HAT activity. Histone

acetylation sites H4K12, H3K9, H3K9K14 and H3K23 tend to become

hyperacetylated and sites H4K8 and H3K18 become hypoacetylated

throughout the aging process inD. melanogaster (Peleg et al., 2016). Decreas-

ing the activity of the acetyl-CoA-synthesizing enzyme ATP citrate lyase or

the level of the H4K12-specific HAT,Chameau, resulted in alleviation of the

aging-associated changes and promoted the flies’ longevity (Peleg et al.,

2016). The overexpression of HAT Tip60 rescued the axonal transport

insufficiency and improved memory in a D. melanogaster model of

Alzheimer’s disease (Johnson et al., 2013; Lorbeck et al., 2011; Xu et al.,

2014).

4.3 Histone DeacetylasesSome studies also suggest that the aging process in D. melanogaster can be

influenced by HDAC activity. For instance, the NAD+-dependent HDAC,

dSir2, was repeatedly shown to be largely involved in calorie restriction-

dependent extension of life span in fruit flies (Rogina and Helfand,

2004). Knockdown of dSir2 in the flies’ adult fat body influences the fat

mobilization and survival in conditions of starvation. Moreover, the knock-

down of dSir2 in the adult fat body leads to increase of expression level of

insulin-like peptide, dilp5, thereby mediating the systemic effects of insulin

signalling (Banerjee et al., 2012a). Knockdown of dSir2 in the adult fat body

was also shown to regulate the flies’ longevity in a diet-dependent manner

(Banerjee et al., 2012b).

4.4 HDAC InhibitorsIn the last few years, a novel class of drugs has been proposed targeting epi-

genetic pathways (epigenetic drugs). The potential reversibility of epigenetic

aberrations makes them attractive targets for therapeutic drug development.

Currently, candidate epigenetic drugs are inhibitors of DNA methylation,

HATs, HDACs, histone methyltransferases, histone demethylases and

bromodomains (Cacabelos and Torrellas, 2015; Heerboth et al., 2014).

Among them, HDAC inhibitors (HDACIs) are likely the most promising



in the field of biogerontology. HDACIs include four chemical classes that

substantially vary in biological activity, structure and specificity: cyclic pep-

tides, hydroxamic acids, short chain fatty acids and synthetic benzamides

(Lakshmaiah et al., 2014). Since the transcription levels of many genes

decrease with age (Seroude et al., 2002), the restoration of the transcriptional

activity by means of HDACIs may likely delay the age-related functional

declines. Furthermore, inhibition of HDAC activity can lead to

upregulation of genes implicated in response to stress and inflammation, i.e.

pathways commonly associated with the regulation of life span (Kourtis and

Tavernarakis, 2011). InD. melanogaster, each HDAC was shown to regulate

transcription of a unique set of genes (Cho et al., 2005), and differential sen-

sitivity of HDACs to HDACIs has been observed. Longevity-modulating

effects of HDACIs have been studied mainly in insect experimental models

such asD. melanogaster (Vaiserman and Pasyukova, 2015). Most studies have

been primarily devoted on the life-extending potential of synthetic

HDACIs, although HDACIs contained in natural compounds may be

promising as well. Examples hereof are sulforaphane, curcumin and diallyl

disulfide extracted from broccoli, turmeric and garlic, respectively. Exper-

imental data supporting the health span-promoting and life span-extending

properties of different HDACIs are reviewed in the subsections later.

4.4.1 PhenylbutyrateSodium 4-phenylbutyrate (PBA) was found to inhibit class I and II HDACs,

thereby leading to elevated gene expression, reduced cellular proliferation,

induction of apoptosis and the enhanced cell differentiation in neoplastic cell

populations (Iannitti and Palmieri, 2011). In D. melanogaster, the life-

extending potential of the sodium salt of PBAwas demonstrated in the study

by Kang et al. (2002). Feeding with PBA substantially extended both mean

and maximal life span by up to 30%–50%, without diminution of locomotor

activity and resistance to stress. The treatment for a limited period, either

early or late in adult life, has been shown to extend the flies’ longevity as

well. This result was not due to caloric restriction, known to extend life span

in different model organisms, or due to the decreased reproductive activity.

The effect of PBA has been also accompanied by marked changes in the

acetylation level of histones H3 and H4 and either down- or upregulation

of several hundreds of genes, as it was evident from the DNA microarray-

based global transcriptional analysis. The general trend was upregulation of

genes involved in detoxification and chaperone activity, including several

genes that have previously been found to be involved in life span



determination in D. melanogaster, and downregulation of genes involved in

different metabolic pathways. These data support the hypothesis that life

span extension may be caused by overall generalized changes in epigenetic

regulation (Vaiserman, 2011).

4.4.2 Sodium ButyrateSodium butyrate (SB) is a short chain fatty acid and has an HDAC inhibition

activity. SB was shown to influence the processes of cell growth, differen-

tiation and apoptosis in both normal and transformed cells (Buommino et al.,

2000; Khan and Jena, 2014). It thus also has a longevity promoting potential.

One-off treatment with SB resulted in significant increase of both mean

and maximum life span (by 25.8% and 11.5%, respectively) of fruit flies

(Zhao et al., 2005a). Subsequently, life-extending ability of SB treatment

in D. melanogaster was demonstrated by other authors (McDonald et al.,

2013; St Laurent et al., 2013; Vaiserman et al., 2012, 2013). In the

McDonald et al. (2013) study, SB-induced life span improvement was

accompanied by an increase of the flies’ locomotor activity. The obtained

effects were dose dependent: treatment with SB in concentrations varying

from 10 to 40mM demonstrated a potential to increase life span, whereas

treatments in doses equal or higher than 100mM decreased longevity

(Vaiserman et al., 2012; Zhao et al., 2005a). In some cases, the effect

observed depended on whether the line used was short- or long-lived

(McDonald et al., 2013; Zhao et al., 2005a). Remarkably, the life-extending

effect obtained was unlikely due to the decreased reproductive performance,

because no reduction in reproductive activity was revealed in SB-treated

females (Vaiserman et al., 2012). The treatment with SB caused elevated

levels of acetylation of histone H3 (Zhao et al., 2005a,b, 2006, 2007),

whereas the level of acetylation of histone H4 remained unchanged

(Zhao et al., 2007). Histone H3 with elevated acetylation levels was found

at the promoter regions of the hsp22, hsp70 and hsp26 genes (Zhao et al.,

2005b, 2006, 2007). SB also affected the chromatin structure at the site of

cytogenetic location of the hsp70 gene on the polythene chromosome

(Chen et al., 2002). The enhanced levels of expression of hsp22, hsp26

and hsp70 genes were accordingly found in the SB-treated flies (Chen

et al., 2002; Zhao et al., 2005a,b, 2006, 2007). Collectively, these findings

suggest that alteration in histone acetylation and, thereafter, in the expres-

sion levels of chaperone genes may contribute to the life-extending effects

of SB and other HDACIs in D. melanogaster. Other mechanisms, however,

may also contribute to these effects. For example, the treatment with



SB-supplemented food rescued the early mortality of the flies with the pes-

ticide rotenone-induced Parkinson’s disease (St Laurent et al., 2013). The

SB-mediated rescue of rotenone-induced Parkinson’s disease was associated

with elevated dopamine levels in the flies’ brains. HDACIs targeting

HDAC3 and HDAC1 have been shown to be able to ameliorate

polyglutamine-elicited phenotypes in a Drosophila model of another age-

related neurodegenerative disorder, Huntington’s disease, as well (Jia

et al., 2012). Upregulation of inducible expression of sir2 gene known to

be substantially involved in the life span extension in D. melanogaster

(Frankel et al., 2011) was also observed after SB treatment (Vaiserman

et al., 2012).

Effects of SB on life span were shown to be depended on the stage and/or

age when treatment was applied. Increased life span was observed after treat-

ment at the larval stage only (Vaiserman et al., 2012, 2013; Zhao et al.,

2005a), whereas treatment at both the larval and the adult stage or exclu-

sively throughout the adult stage either decreased life span (McDonald

et al., 2013), or increased it (Vaiserman et al., 2012, 2013) or had no effect

on longevity (Zhao et al., 2005a). Furthermore, life span-modulating effects

of SB were shown to be sex specific (Vaiserman et al., 2012, 2013). To

explain these inconsistencies in the effects of SB and other epigenetic mod-

ulators on the flies’ life span, a hypothesis was proposed suggesting phase sep-

aration in the adult life of fruit fly and other gradually aging organisms into a

health span, a transition phase, and a senescent span (Arking et al., 2002). In

analysis conducted by Arking (2009) in D. melanogaster and other model

organisms, it has been shown that these life stages are characterized by dif-

ferent gene expression patterns. The health span is characterized by a tightly

regulated gene expression pattern which leads to a maximized tissue func-

tion and to a minimized inflammatory and other damage response; the tran-

sition phase is characterized by a gradual decline of the cellular regulatory

capacity, and the senescent span is characterized by a gradual deregulation

of the gene expression pattern (Arking, 2009). Consistently with this

hypothesis, the flies’ life span was increased when flies were fed with SB dur-

ing transition or senescent spans, but it was decreased when SB was admin-

istered throughout the entire adult life span or the health span only

(McDonald et al., 2013). Similar results were demonstrated in flies fed with

another compound known to inhibit HDAC activity, curcumin (Arking,

2015). To summarize, despite the complexity and partial inconsistency of

results, SB demonstrated a high potential as a life-extending agent in

Drosophila.



4.4.3 Trichostatin ATrichostatin A (TSA) is another widely used HDACI demonstrating a broad

spectrum of epigenetic activities, including inhibition of the cell cycle since

the beginning of the growth stage and promotion of the expression of

apoptosis-associated genes (Vanhaecke et al., 2004). TSA is recognized as

a promising anticancer drug candidate. Possible mechanisms of action of this

compound are induction of terminal differentiation, cell cycle arrest and

apoptosis in different cancer cell lines and thereby inhibition of

tumorigenesis.

The epigenetic and phenotypic effects of the TSA treatment are very

similar to those shown for the SB treatment in D. melanogaster. An increase

of both mean and maximum life span was observed due to both one-off and

continuous treatment with TSA (Tao et al., 2004; Zhao et al., 2005a). TSA

treatment was effective both at the larval (Zhao et al., 2005a) and adult (Tao

et al., 2004) stages and influenced the longevity of both short- and long-lived

D. melanogaster lines, but to a different extent. Life span improvement

affected both males and females and was in some cases accompanied by

increase in locomotor activity. These life-extending effects induced by

the TSA treatment were accompanied by the hyperacetylation of core his-

tone H3 in the promoter and coding regions of some chaperone genes, such

as hsp22, hsp26 and hsp70, along with upregulation, in most cases, of both

basal and inducible expression of these genes (Chen et al., 2002; Tao et al.,

2004; Zhao et al., 2005a,b, 2006, 2007). Moreover, the modified chromatin

morphology at the locus of hsp22 was revealed (Tao et al., 2004). The

authors suggested that the expression of chaperones can stimulate the repair

mechanisms, reduce the level of accumulation of damage and improve the

cell stress resistance to create cellular and physiological environments that are

favourable for longevity. To summarize, TSA similarly to SB demonstrated a

high potential as a life-extending agent in D. melanogaster.

4.4.4 Suberoylanilide Hydroxamic AcidOne more HDACI that was shown to be able to extend life in fruit flies, is

suberoylanilide hydroxamic acid (SAHA). In in vitro studies, SAHA was

found to have similar effects as does SB although at much lower effective

doses (Zhou et al., 2011). This compound was demonstrated to induce

growth arrest in transformed cells (Yin et al., 2007), and it was shown to

be effective in preventing Huntington disease in various animal models

(Steffan et al., 2001).



Effects of administration with SAHA throughout D. melanogaster health

span, transition phase and senescent span have been studied (McDonald

et al., 2013). Treatment with SAHA during the transition or senescent spans

resulted in decreased mortality rate and extended longevity compared to the

control, while supplementation during the entire adult life span or during

the health span only led to decreased longevity in the normal-lived strain.

The analysis of mortality curves indicated that there were no significant

effects of the SAHA administration until the age of �50 days. When the

long-lived strain was administered with SAHA by the same scheme, mostly

deleterious effects were detected. Remarkably, the SAHA-treated normal-

lived D. melanogaster strain showed the late-life-extending effects similar to

those seen in the same study for SB. The fact that two different HDACIs, SB

and SAHA, had similar effects on mortality rate during the senescent span

indicates the similarity of mechanisms that underlie beneficial effects for this

class of HDACIs. The authors suggested that HDACIs may significantly

influence the mortality rate throughout the senescent phase by reducing

the vulnerability of treated individuals, in a manner similar to that of dietary

restriction. Indeed, as it was mentioned earlier, genetic alterations in genes

encoding HDACs and nutrition regiments partially interact in the course of

longevity control (Frankel et al., 2015; Rogina and Helfand, 2004).

In conclusion, HDACIs may likely affect several pathways involved in

regulating gene expression patterns associated with healthy aging. The

induction of these patterns of gene expression throughout senescence when

they are not normally present may likely underlie the life-extending effects

of HDACIs.

5. TRANSGENERATIONAL EPIGENETIC INHERITANCEOF LIFE SPAN AND LONGEVITY-ASSOCIATEDTRAITS IN DROSOPHILA

Compelling evidence for the role of epigenetic mechanisms in life

span determination has been obtained in recent studies demonstrating the

possibility of nongenomic transmission of longevity phenotypes across gen-

erations. Traditionally, epigenetic marks, such as DNAmethylation, are not

thought to be inherited into subsequent generations, since they are assumed

to be completely erased and then reestablished in each generation. Accumu-

lating evidence, however, indicates that many effects may be transmitted

across generations via nongenetic factors. Such effects are commonly

referred to as ‘intergenerational’ or ‘transgenerational’ effects (Fig. 2).



The clear distinction between the genetic (hard) and epigenetic (soft)

inheritance is that epigenetic modifications, unlike the genetic ones, are

reversible and may persist for few (usually 3–4) generations only in the

absence of triggering stimulus (Lim and Brunet, 2013). Many recent

Sperm Egg

F0

Intergenerationalinheritance

Environmentaltrigger

Transgenerationalinheritance

Transgenerationalinheritance

Intergenerationalinheritance

F0

F1 F1

F2 F2

F3...

F4...

F3

Fig. 2 Schematic representation of intergenerational and transgenerational effects inD. melanogaster. In the case of intergenerational inheritance, parental exposuresdirectly influence the offspring’s germ cells. By contrast, transgenerational effects occurin the F3 and subsequent generations arising from the F2 generation germline that hasnot been directly exposed to the triggering environmental stimuli.



investigations highlighted the central role of epigenetic mechanisms in

mediating such effects. These processes are believed to include altered pat-

terns of DNA methylation and histone posttranslational modifications, and

also changed expression of noncoding RNAs causing modified local acces-

sibility to the genetic material and modulated gene expression (Pal and

Tyler, 2016). In some recent studies, the importance of nongenomic trans-

generational effects in inheritance of age-related characteristics has been

highlighted (for a review, see Li and Casanueva, 2016). However, trans-

generational effects on life span have hitherto only been reported rarely.

Most papers reviewing and discussing these effects are solely focused on

findings from the nematode Caenorhabditis elegans (Benayoun and Brunet,

2012; Berger, 2012; Pang and Curran, 2012), although similar data have

been obtained from insect species as well. High-sugar maternal diet chan-

ged the offspring larval body composition for at least two generations

in D. melanogaster, thereby causing development of obese-like phenotype

in adult offspring maintained under high-calorie dietary conditions

(Buescher et al., 2013). The levels of expression of metabolic genes (known

to be substantially related to longevity) have been largely modified in the

offspring of affected flies. Transgenerational effects on longevity and repro-

duction induced by posteclosion nutritional manipulations with low-,

intermediate- or high-protein contents in the ancestral population have

been demonstrated (Xia and de Belle, 2016). Both low-protein and high-

protein diets decreased life span, while the intermediate-protein diet

extended life span until the F3 generation. Similar effects were also observed

with respect to the female reproductive activity which was found to be

reduced in the low-protein groups and enhanced in the intermediate-

protein groups in F0–F2 generations. In a subsequent study by the same

authors, ancestral exposure to a low-protein diet throughout the post-

eclosion period resulted in the upregulation of the H3K27-specific methyl-

transferase, E(z), thereby causing increased H3K27 trimethylation

(H3K27me3) levels (Xia et al., 2016). These changes were accompanied

by a longevity shortening in F0 generation as well as in the F2 offspring gen-

eration. Both RNAi-mediated knockdown of E(z) and pharmacological

inhibition of its enzymatic function by a histone methyltransferase inhibitor

Tazemetostat (EPZ-6438) resulted in lower levels of H3K27me3 across sev-

eral generations. Moreover, the exposure to EPZ-6438 entirely mitigated

the longevity-shortening effect of the parental exposure to a low-

protein diet.



Cross-generational effects have also been shown in fruit flies with regard

to factors other than nutrition. Cross-life stage and cross-generational adap-

tive plasticity induced by gamma irradiation at the egg stage was observed

(Vaiserman et al., 2004). This cross-generational plasticity exhibited in

enhanced resistance to starvation and heat shock stresses, as well as in

extended life span in the F0 and F1 generations of D. melanogaster. Cross-

generational impact of radiation exposure in ancestral F0 generation on

the life span in F1 and F2 generations was also demonstrated (Shameer

et al., 2015). Paternal exposure to small-to-moderate radiation doses

(1–10Gy) lead to an increased life span in both male and female offspring,

while exposure to higher doses (40 and 50Gy) resulted in shortening the

descendant longevity. These transgenerational effects persisted up to F2 gen-

eration and completely disappeared in the F3 generation.

Collectively, these findings suggest that particular nongenetic factors,

apparently epigenetic in origin, can influence longevity in D. melanogaster

not only in affected generation but also in several subsequent generations.

6. CONCLUSIONS

Aging is a complex process influenced by a large number of environ-

mental and genetic factors and their interactions that are far from understood.

The effects of these factors are difficult to separate because they influence and

modify each other. Therefore, it is difficult to investigate each of these factors

separately, especially by using complexmammalianmodels like rodents, and a

large part of modern biogerontological research is based on simpler model

organisms, mainly yeast, nematodes and insects (Parrella and Longo, 2010).

The use of simple model organisms including insects seems particularly useful

in an exceedingly complex field such as epigenetics of aging. Thesemodels are

inexpensive tomaintain, have short generation times and no associated ethical

issues. Moreover, a high degree of conservation exists between insect and

mammalian genomes in terms of both epigenetic mechanisms and signalling

pathways associated with development, immunity and disease.

The importance of epigenetic mechanisms including DNAmethylation,

histone modifications and the expression of miRNAs in aging and longevity

of many insect species has been highlighted repeatedly. In particular, social

insects provide many amazing examples of phenotypic plasticity controlled

by epigenetic mechanisms, producing different longevity phenotypes from

the same genotype by transcriptional reprogramming during development.



Thus, insects can provide very valuable models to investigate the epigenetic

factors mediating the influence of environmental factors on development,

aging, neurodegeneration, cancer and infectious disorders (Mukherjee

et al., 2015). Therefore, the identification of epigenetic processes underlying

aging and aging-related pathological conditions, such as inflammation, neu-

rodegeneration and cancer, in insect models seems to be an important step

towards the further development of treatment strategies to promote human

health span and longevity.

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